Advisor(s)
Malgorzata Kasztan
David Pollock
Committee Member(s)
Adam Wende
Jeffrey Lebensburger
Shannon Bailey
Subhashini Bolisetty
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Joint Health Sciences
Date of Award
9-11-2025
Abstract
Background: Sickle cell disease (SCD) is a hematologic disorder resulting in hemolysis of red blood cells and iron overload in multiple tissues in the body, including the kidney. Iron is known to generate reactive oxygen species that may lead to oxidative stress-dependent ferroptosis. In addition, mitochondria are a prominent target for iron overload-mediated damage. Nonetheless, the impact of intravascular hemolysis-mediated iron overload on the kidney in SCD has yet to be elucidated. Methods: A humanized mouse model of sickle cell disease (HbSS) was used to study the impact of kidney-specific iron overload on renal injury. Both male and female HbSS and genetic control (HbAA) mice were administered an iron chelator, deferiprone (DFP) to examine the impact of excess iron removal on renal injury, features of ferroptosis, and mitochondrial function. Results: Iron chelation preserved kidney function in males and prevented the progression of proteinuria in both male and female HbSS mice. DFP treatment also prevented the progression of glomerulosclerosis, preserved brush border integrity, and reduced F4/80+ cells accumulation in renal cortex of HbSS mice. Oxidative stress was observed in the renal cortex of both male and female HbSS mice, but without ferroptosis. In addition, basal mitochondrial respiration was decreased in male HbSS mice in comparison to male HbAA mice, while female HbSS mice showed superior bioenergetic profile than male HbSS mice. Iron chelation did not improve oxidative stress in male and female HbSS mice or mitochondrial dysfunction in male HbSS mice. Conclusion: Renal iron overload mediates kidney injury in HbSS mice. Oxidative stress is not mediated by iron overload and ferroptosis is not an implicated mode of cell death in the renal cortex of HbSS mice. Mitochondrial dysfunction presents only in male HbSS mice and is not ameliorated by iron chelation therapy.
ProQuest ID
Recommended Citation
Sako, Mohammad, "Impact Of Renal Iron Overload On Sickle Cell Nephropathy" (2025). All ETDs from UAB. 7350.
https://digitalcommons.library.uab.edu/etd-collection/7350
